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Modelling Amyloidosis in Mice

Slamova, I; (2016) Modelling Amyloidosis in Mice. Doctoral thesis , UCL (University College London). Green open access

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Abstract

Amyloidosis is a group of disorders in which specific soluble proteins convert into insoluble extracellular fibrillar deposits. Certain mutations in amyloid prone proteins result in aggressive forms of the disease. β2-microglobulin (β2m), a cell surface protein and transthyretin (TTR), a normal plasma protein, are inherently amyloidogenic. In patients undergoing long-term dialysis, ineffective clearance of β2m from the plasma results in sustained increase of its concentration and its deposition as amyloid. Wild type TTR is the amyloid precursor in senile systemic amyloidosis, a cause of heart failure in the elderly, and various different mutations in the human TTR gene cause the autosomal dominant conditions familial amyloid polyneuropathy and familial amyloid cardiomyopathy. The D76N β2m variant causes highly penetrant hereditary systemic amyloidosis. Similarly, the S52P TTR variant also causes aggressive amyloidosis which is characterised by prominent cardiac ATTR deposits. Animal models for Aβ2m amyloidosis and ATTR amyloidosis have long been sought to enable a better understanding of disease mechanisms and for validation of diagnostic methods and treatments, but previous attempts to model these diseases in vivo have met with limited or no success. The aims of this project were to generate mouse models of: (1) Aβ2m amyloidosis and (2) cardiac ATTR amyloidosis by transgenic expression of these highly amyloidogenic variants. In the work presented here, hβ2mD76N transgenic mice and hTTRS52P transgenic mice were generated. Despite expressing high plasma concentrations of the amyloidogenic proteins, the mice did not spontaneously develop amyloidosis. After priming amyloid deposition with pre formed amyloid fibrils, the hβ2mD76N transgenic mice failed to develop amyloid deposits. It is notable that most of the β2m circulates bound in a complex, potentially limiting the availability of free β2m monomers for conversion into fibrils. In the hTTRS52P transgenic mice, priming of amyloid deposition with amyloid fibrils led to consistent and reproducible development of cardiac ATTR amyloidosis.

Type: Thesis (Doctoral)
Title: Modelling Amyloidosis in Mice
Event: University College London
Open access status: An open access version is available from UCL Discovery
Language: English
Keywords: Amyloidosis, β2-microglobulin, Transthyretin, Animal model
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inflammation
URI: https://discovery.ucl.ac.uk/id/eprint/1534595
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